Programmed cell death, or apoptosis, plays a crucial role throughout the life of all multicellular organisms. This mechanism allows for the controlled removal of cells during development in sculpturing the body, maintaining body structure and tissue size, and is also used for eliminating damaged or infected cells. Apoptosis has to be a tightly regulated process or else various abnormalities and diseases may arise from either too much or too little cell death. These include various developmental defects, neurodegenerative diseases, autoimmune diseases and cancer. Central to this process are a family of cysteine proteases called caspases. Their activation leads to the typical morphological changes that occur during apoptosis and thus their regulation is key for proper control of apoptosis. The objectives of this proposal is to provide the structural framework which will enable us to understand the mechanism by which caspases are activated from their inactive, zymogen form to a fully active enzyme, and how these relate to enzymatic activity and ultimately to cellular function. We will focus specifically on caspase-9 activation.